Redox equilibrium of serum apolipoprotein E3: a buffering effect of disulfide-linked complexes against oxidative stress on apolipoprotein E3–containing lipoproteins
Open accessAbstract
Reversible redox modification of cysteine thiols is crucial for protecting proteins from irreversible detrimental change. However, the physiological significance of the redox modification of apolipoprotein (apo) E is unclear. Here, we hypothesized that the disulfide-linked complexes of apoE3 corresponding to the representative reversible-modified apoE3 play a protective role against oxidative stress. The effects of disulfide bond formation on oxidative stress on apoE3 were evaluated with a band-shift assay. Maleimide-labeled apoE3 and unlabeled apoE3 were defined as the reduced (r)-apoE3 and non-reduced (nr)-apoE3 forms, respectively. Hydrogen peroxide-induced oxidation decreased for reduced-form apoE (r-apoE3) but increased for nr-apoE3. Induction of apoE3-AII complex formation with excess of apoAII markedly suppressed the oxidative stress-induced increase in nr-apoE3 (P<0.001) and enhanced homodimer formation. The apoE3-AII complex was more dominant in high-density lipoprotein (HDL) than in very low-density lipoprotein. Under oxidative stress, HDL showed a significant decrease, rather than an increase, in nr-apoE3 levels with a concomitant significant increase in apoE3-AII levels (P<0.005). This finding suggests that the majority of nr-apoE3 in HDL exists in a reversible oxidized form. The apoE3-AII complex, formed from the reversible oxidized apoE3, is beneficial for maintaining the redox equilibrium of apoE3 by preventing the modification of apoE3 to its irreversible oxidized form. The apoE3-AII complex may be possibly implicated in the pathophysiology of various apoE-related diseases.
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Cysteine-dependent ApoE3 homodimers and ApoE3-apoA-II complexes have been linked to HDL-related behavior and redox buffering.
“These cysteine-dependent ApoE3 homodimers and ApoE3-apoA-II complexes have been linked to HDL-related behavior and redox buffering (44,45), and plasma ApoE homodimer levels are reduced in APOEε3-carrying AD patients relative to controls (43), suggesting that these disulfide-linked species may themselves be functionally relevant in ways not captured by the NanoBiT assay.”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [45]
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Andrieieva, D., Falltrick, I., Chiang, C.-Y., Beaumont, B., Guen, Y. L., Liu, C., Pergolesi, S., Ma, C.-T., Jackson, M. R., Hyman, B. T., et al. (2026) · doi:10.64898/2026.05.09.26352797 · Cited by 2 · see citing works
- Authors
- Yamauchi, K., Iwasaki, S., & Kawakami, Y.
- Affiliations
- University of Tsukuba (JP)
- Corresponding author
- Yamauchi, Kazuyoshi
- ORCID
- Yamauchi, Kazuyoshi
- Venue
- Bioscience Reports
- Publisher
- Portland Press Ltd.
- Published
- 2019-04
- Volume
- 39
- Issue
- 4
- Pages
- BSR20190184
- ISSN
- 0144-8463 (ISSN-L)
- 1573-4935
- PMC
- PMC6488860
- OpenAlex
- W2931017505
- Cited by
- 7
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 1
- FWCI
- 0.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Bioscience Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (acceptedVersion, cc-by)
- Terrestrial Environment Research Center (University of Tsukuba) (submittedVersion, cc-by)
- Funders
- Japan Society for the Promotion of Science (18K07461)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E3, apolipoprotein A-II, redox equilibria, oxidative stress, hydrogen peroxide, high-density lipoprotein, VLDL, protein homodimerization
- MeSH terms
- Apolipoproteins E, Disulfides, Humans, Hydrogen Peroxide, Lipoproteins, HDL, Lipoproteins, VLDL, Maleimides, Oxidation-Reduction, Oxidative Stress, Protein Isoforms, Apoprotein(a), Healthy Volunteers
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